AIPL1

Chr 17ADAR

AIP like 1 HSP90 co-chaperone

Also known as: AIPL2, LCA4

NCBI Gene: 23746 ENSG00000129221 UniProt: Q9NZN9

Leber congenital amaurosis (LCA) is the most severe inherited retinopathy with the earliest age of onset and accounts for at least 5% of all inherited retinal diseases. Affected individuals are diagnosed at birth or in the first few months of life with nystagmus, severely impaired vision or blindness and an abnormal or flat electroretinogram. The photoreceptor/pineal-expressed gene, AIPL1, encoding aryl-hydrocarbon interacting protein-like 1, is located within the LCA4 candidate region. The encoded protein contains three tetratricopeptide motifs, consistent with chaperone or nuclear transport activity. Mutations in this gene may cause approximately 20% of recessive LCA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Primary Disease Associations & Inheritance

Cone-rod dystrophyMIM #604393

ADAR

Leber congenital amaurosis 4MIM #604393

ADAR

Retinitis pigmentosa, juvenileMIM #604393

ADAR

532

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— AIPL1

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Gene-Disease Validity (ClinGen)

AIPL1-related retinopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

88 Pathogenic / Likely Pathogenic· 204 VUS of 532 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.07LOEUF

pLI 0.000

Z-score 1.37

OE 0.63 (0.39–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.08Z-score

OE missense 0.99 (0.89–1.10)

235 obs / 238.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.63 (0.39–1.07)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.89–1.10)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96

0≤1.21.6

LoF obs/exp: 10 / 15.9Missense obs/exp: 235 / 238.4Syn Z: 0.31